Immunotherapeutic agents use or modify immune mechanisms. Use of these agents is rapidly evolving; new classes, new agents, and new uses of current agents are certain to be developed. A number of different classes of immunotherapeutic agents have been developed (see Table 4: Biology of the Immune System: Some Immunotherapeutic Agents in Clinical Use* ):

• Monoclonal antibodies
• Fusion proteins
• Soluble cytokine receptors
• Recombinant cytokines
• Small-molecule mimetics
• Cellular therapies

Table 4
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Some Immunotherapeutic Agents in Clinical Use*  Agent Effects Indications Monoclonal antibodies Adalimumab Anti–TNF-α Moderate to severe RA Plaque psoriasis Moderate to severe Crohn disease refractory to standard treatments Ankylosing spondylitis Psoriatic arthritis Moderate to severe polyarticular juvenile idiopathic arthritis Alemtuzumab Anti–B cell (CD52) B-cell chronic lymphocytic leukemia refractory to standard treatments Basiliximab Anti–IL-2 receptor Prevention of acute kidney rejection Belimumab Anti–B-lymphocyte stimulator protein (anti-BLyS) Active, autoantibody-positive SLE in adults receiving standard treatment Brentuximab vedotin Anti-CD30 (linked to the antimitotic agent monomethyl auristatin E) Hodgkin lymphoma after failure of autologous stem cell transplantation (ASCT) or of at least 2 multidrug chemotherapy regimens in patients who are not candidates for ASCT Systemic anaplastic large cell lymphoma after failure of at least one multidrug chemotherapy regimen Certolizumab (pegylated Fab' fragment) Anti–TNF-α Moderate to severe active RA in adults Moderate to severe Crohn disease if response to conventional treatments is inadequate Daclizumab Anti–IL-2 receptor Prevention of acute kidney rejection Eculizumab Anti–complement component C5 Paroxysmal nocturnal hemoglobinuria Atypical hemolytic uremic syndrome Ibritumomab Anti–B cell (CD20; linked to the radioactive agent yttrium 90) Relapsed or refractory low-grade follicular or transformed B-cell non-Hodgkin lymphoma Infliximab Anti–TNF-α Moderate to severe Crohn disease or ulcerative colitis if response to conventional treatments is inadequate Moderate to severe RA (used with methotrexate) Active ankylosing spondylitis Active psoriatic arthritis Chronic severe plaque psoriasis when other treatments are less appropriate ANCA-associated nephritis (eg, due to granulomatosis with polyangiitis [Wegener granulomatosis] or microscopic polyangiitis) Ipilimumab Anti–CTLA-4 Inoperable or metastatic advanced melanoma Mepolizumab Anti–IL-5 Eosinophilic dermatitis in hypereosinophilic syndrome Muromonab-CD3 (OKT3) Anti–T cell (CD3) Acute treatment of heart, kidney, or liver transplant rejection Natalizumab Anti–α4-integrin subunit Relapsing multiple sclerosis or Crohn disease when other treatments are inadequate Ofatumumab Anti‒B cell (CD20) CLL refractory to fludarabine and alemtuzumab Omalizumab Anti-IgE Moderate to severe asthma in patients > 12 yr with documented allergic disorders inadequately controlled by inhaled corticosteroids Pexelizumab Anti–complement component C5 Coronary artery bypass graft surgery requiring cardiopulmonary bypass Rituximab Anti–B cell (CD20) Relapsed or refractory CD20+, low-grade or follicular B-cell non-Hodgkin lymphoma CD20+ CLL (used with fludarabine and cyclophosphamide) Moderate to severe RA (used with methotrexate) when response to TNF-antagonists is inadequate Granulomatosis with polyangiitis (Wegener granulomatosis) Microscopic polyangiitis Tocilizumab Anti–IL-6 receptor (anti–IL-6R) Moderate to severe RA when response to TNF-antagonists is inadequate Tositumomab Anti–B cell (CD20; linked to radioactive iodine [131I]) Refractory and relapsed CD20+ low-grade follicular or transformed non-Hodgkin lymphoma Ustekinumab Anti-IL12 and -IL 23 Moderate to severe plaque psoriasis Fusion proteins Abatacept (CTLA-4 extracellular domain fused to the Fc region of IgG1) Inhibition of T-cell activation Moderate to severe RA Alefacept (fusion of CD2-binding portions of CD58 to Fc region of IgG1) Inhibition of T-cell activation; induction of T-cell apoptosis Moderate to severe chronic plaque psoriasis Denileukin diftitox (fusion of IL-2 to diphtheria toxin) Delivery of toxin to CD25 component of IL-2 receptor CD25+ cutaneous T-cell lymphoma Etanercept (fusion of 2 CD120b TNF-α receptors to Fc region of IgG1) Decrease in TNF levels Moderate to severe RA Polyarticular juvenile RA Psoriatic arthritis Active ankylosing spondylitis In patients ≥ 18 yr: Chronic moderate to severe plaque psoriasis Soluble cytokine receptor Anakinra (IL-1 receptor antagonist, sometimes pegylated for longer half-life) Competitive inhibition of IL-1α and IL-1β activities In patients ≥ 18 yr: Moderate to severe RA, Still disease, some periodic fevers Cytokines IFN-α Antiproliferative and antiviral In patients ≥ 18 yr: Chronic hepatitis C, AIDS-related Kaposi sarcoma, hairy cell leukemia, chronic myelogenous leukemia, metastatic melanoma IFN-β Antiproliferative and antiviral Reduction of number of flare-ups in relapsing multiple sclerosis IFN-γ Immunostimulatory and antiviral Control of infection in chronic granulomatous disease, delay of progression in severe malignant osteopetrosis IL-2 Immunostimulatory Renal cell carcinoma and metastatic melanoma IL-11 Thrombopoietic growth factor Prevention of thrombocytopenia after myelosuppressive chemotherapy G-CSF Stimulation of granulocyte production Reversal of neutropenia after chemotherapy, radiation therapy, or both GM-CSF Stimulation of granulocyte and monocyte/macrophage production Reversal of neutropenia after chemotherapy, radiation therapy, or both Cellular therapy Sipuleucel-T Autologous circulating ICAM-1+ peripheral blood mononuclear cells activated with prostatic acid phosphatase and GM-CSF Asymptomatic or minimally symptomatic metastatic prostate cancer refractory to castration (hormone therapy) *mAbs used for diagnostic testing and radiologic imaging are not included. ANCA = antineutrophil cytoplasmic antibodies; CD = cluster of differentiation; CLL = chronic lymphocytic leukemia; CTLA = cytotoxic T-lymphocyte antigen; Fc = crystallizable fragment; G-CSF = granulocyte colony-stimulating factor; GM-CSF = granulocyte-macrophage colony-stimulating factor; ICAM = intercellular adhesion molecule; IFN = interferon; mAb = monoclonal antibody; TNF = tumor necrosis factor. Some Immunotherapeutic Agents in Clinical Use*  Agent Effects Indications Monoclonal antibodies Adalimumab Anti–TNF-α Moderate to severe RA Plaque psoriasis Moderate to severe Crohn disease refractory to standard treatments Ankylosing spondylitis Psoriatic arthritis Moderate to severe polyarticular juvenile idiopathic arthritis Alemtuzumab Anti–B cell (CD52) B-cell chronic lymphocytic leukemia refractory to standard treatments Basiliximab Anti–IL-2 receptor Prevention of acute kidney rejection Belimumab Anti–B-lymphocyte stimulator protein (anti-BLyS) Active, autoantibody-positive SLE in adults receiving standard treatment Brentuximab vedotin Anti-CD30 (linked to the antimitotic agent monomethyl auristatin E) Hodgkin lymphoma after failure of autologous stem cell transplantation (ASCT) or of at least 2 multidrug chemotherapy regimens in patients who are not candidates for ASCT Systemic anaplastic large cell lymphoma after failure of at least one multidrug chemotherapy regimen Certolizumab (pegylated Fab' fragment) Anti–TNF-α Moderate to severe active RA in adults Moderate to severe Crohn disease if response to conventional treatments is inadequate Daclizumab Anti–IL-2 receptor Prevention of acute kidney rejection Eculizumab Anti–complement component C5 Paroxysmal nocturnal hemoglobinuria Atypical hemolytic uremic syndrome Ibritumomab Anti–B cell (CD20; linked to the radioactive agent yttrium 90) Relapsed or refractory low-grade follicular or transformed B-cell non-Hodgkin lymphoma Infliximab Anti–TNF-α Moderate to severe Crohn disease or ulcerative colitis if response to conventional treatments is inadequate Moderate to severe RA (used with methotrexate) Active ankylosing spondylitis Active psoriatic arthritis Chronic severe plaque psoriasis when other treatments are less appropriate ANCA-associated nephritis (eg, due to granulomatosis with polyangiitis [Wegener granulomatosis] or microscopic polyangiitis) Ipilimumab Anti–CTLA-4 Inoperable or metastatic advanced melanoma Mepolizumab Anti–IL-5 Eosinophilic dermatitis in hypereosinophilic syndrome Muromonab-CD3 (OKT3) Anti–T cell (CD3) Acute treatment of heart, kidney, or liver transplant rejection Natalizumab Anti–α4-integrin subunit Relapsing multiple sclerosis or Crohn disease when other treatments are inadequate Ofatumumab Anti‒B cell (CD20) CLL refractory to fludarabine and alemtuzumab Omalizumab Anti-IgE Moderate to severe asthma in patients > 12 yr with documented allergic disorders inadequately controlled by inhaled corticosteroids Pexelizumab Anti–complement component C5 Coronary artery bypass graft surgery requiring cardiopulmonary bypass Rituximab Anti–B cell (CD20) Relapsed or refractory CD20+, low-grade or follicular B-cell non-Hodgkin lymphoma CD20+ CLL (used with fludarabine and cyclophosphamide) Moderate to severe RA (used with methotrexate) when response to TNF-antagonists is inadequate Granulomatosis with polyangiitis (Wegener granulomatosis) Microscopic polyangiitis Tocilizumab Anti–IL-6 receptor (anti–IL-6R) Moderate to severe RA when response to TNF-antagonists is inadequate Tositumomab Anti–B cell (CD20; linked to radioactive iodine [131I]) Refractory and relapsed CD20+ low-grade follicular or transformed non-Hodgkin lymphoma Ustekinumab Anti-IL12 and -IL 23 Moderate to severe plaque psoriasis Fusion proteins Abatacept (CTLA-4 extracellular domain fused to the Fc region of IgG1) Inhibition of T-cell activation Moderate to severe RA Alefacept (fusion of CD2-binding portions of CD58 to Fc region of IgG1) Inhibition of T-cell activation; induction of T-cell apoptosis Moderate to severe chronic plaque psoriasis Denileukin diftitox (fusion of IL-2 to diphtheria toxin) Delivery of toxin to CD25 component of IL-2 receptor CD25+ cutaneous T-cell lymphoma Etanercept (fusion of 2 CD120b TNF-α receptors to Fc region of IgG1) Decrease in TNF levels Moderate to severe RA Polyarticular juvenile RA Psoriatic arthritis Active ankylosing spondylitis In patients ≥ 18 yr: Chronic moderate to severe plaque psoriasis Soluble cytokine receptor Anakinra (IL-1 receptor antagonist, sometimes pegylated for longer half-life) Competitive inhibition of IL-1α and IL-1β activities In patients ≥ 18 yr: Moderate to severe RA, Still disease, some periodic fevers Cytokines IFN-α Antiproliferative and antiviral In patients ≥ 18 yr: Chronic hepatitis C, AIDS-related Kaposi sarcoma, hairy cell leukemia, chronic myelogenous leukemia, metastatic melanoma IFN-β Antiproliferative and antiviral Reduction of number of flare-ups in relapsing multiple sclerosis IFN-γ Immunostimulatory and antiviral Control of infection in chronic granulomatous disease, delay of progression in severe malignant osteopetrosis IL-2 Immunostimulatory Renal cell carcinoma and metastatic melanoma IL-11 Thrombopoietic growth factor Prevention of thrombocytopenia after myelosuppressive chemotherapy G-CSF Stimulation of granulocyte production Reversal of neutropenia after chemotherapy, radiation therapy, or both GM-CSF Stimulation of granulocyte and monocyte/macrophage production Reversal of neutropenia after chemotherapy, radiation therapy, or both Cellular therapy Sipuleucel-T Autologous circulating ICAM-1+ peripheral blood mononuclear cells activated with prostatic acid phosphatase and GM-CSF Asymptomatic or minimally symptomatic metastatic prostate cancer refractory to castration (hormone therapy) *mAbs used for diagnostic testing and radiologic imaging are not included. ANCA = antineutrophil cytoplasmic antibodies; CD = cluster of differentiation; CLL = chronic lymphocytic leukemia; CTLA = cytotoxic T-lymphocyte antigen; Fc = crystallizable fragment; G-CSF = granulocyte colony-stimulating factor; GM-CSF = granulocyte-macrophage colony-stimulating factor; ICAM = intercellular adhesion molecule; IFN = interferon; mAb = monoclonal antibody; TNF = tumor necrosis factor.

Monoclonal antibodies

Monoclonal antibodies (mAbs) are manufactured in vitro to recognize specific targeted Ags; they are used to treat solid and hematopoietic tumors and inflammatory disorders. The mAbs that are currently in clinical use include

• Murine
• Chimeric
• Humanized

Murine mAbs are produced by injecting a mouse with an Ag, harvesting its spleen to obtain plasma cells that are producing Ab specific to that Ag, fusing those cells with immortal mouse myeloma cells, growing these hybridoma cells (eg, in cell culture), and harvesting the Ab. Although mouse antibodies are similar to human antibodies, clinical use of murine mAbs is limited because they induce human anti-mouse Ab production, can cause immune complex serum sickness (a type III hypersensitivity reaction), and are rapidly cleared. An exception is muromonab-CD3 (OKT3), which effectively prevents acute rejection of solid organ transplants; it is typically given only once or twice to a patient receiving other immunosuppressants (see Transplantation: Monoclonal antibodies (mAbs)).

To minimize the problems due to use of pure mouse Ab, researchers have used recombinant DNA techniques to create monoclonal Abs that are part human and part mouse. Depending on the proportion of the Ab molecule that is human, the resultant product is termed chimeric or humanized. In both cases, the process usually begins as above with production of mouse hybridoma cells that make Ab to the desired Ag. Then the DNA for some or all of the variable portion of the mouse Ab is merged with DNA for human immunoglobulin. The resultant DNA is placed in a mammalian cell culture, which then expresses the resultant gene, producing the desired Ab. If the mouse gene for the whole variable region is spliced next to the human constant region, the product is termed "chimeric"; if only parts of the mouse gene for the binding portion of the variable region are used, the product, termed "humanized," is even more human.

Chimeric mAbs activate Ag-presenting cells (APCs) and T cells more effectively than murine mAbs but can still induce production of human anti-chimeric Ab.

Humanized mAbs against various antigens (Ags) have been approved for the treatment of colorectal and breast cancer, leukemia, allergy, autoimmune disease, transplant rejection, and respiratory syncytial virus infection.

Fusion proteins

These hybrid proteins are created by linking together the gene sequences encoding all or part of 2 different proteins to generate a chimeric polypeptide that incorporates desirable attributes from the parent molecules (eg, a cell targeting component combined with a cell toxin). The circulating half-life of therapeutic proteins can also often be improved by fusing them to another protein that naturally has a longer serum half-life (eg, the Fc region of IgG).

Soluble cytokine receptors

Soluble versions of cytokine receptors are used as therapeutic reagents. They can block the action of cytokines by binding with them before they attach to their normal cell surface receptor.

Etanercept, a fusion protein, consists of 2 identical chains from the CD120b receptor for tumor necrosis factor (TNF)-α. This agent thus blocks TNF-α and is used to treat RA refractory to other treatments, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis.

Soluble IL receptors (eg, those for IL-1, IL-2, IL-4, IL-5, and IL-6) are being developed for treatment of inflammatory and allergic disorders and cancer.

Recombinant cytokines

Colony-stimulating factors (CSF), such as erythropoietin, granulocyte CSF (G-CSF), and granulocyte-macrophage CSF (GM-CSF), are used in patients undergoing chemotherapy or transplantation for hematologic disorders and cancers (see Table 4: Biology of the Immune System: Some Immunotherapeutic Agents in Clinical Use* ). Interferon-α (IFN-α) and IFN-γ are used to treat cancer, immunodeficiency disorders, and viral infections; IFN-β is used to treat relapsing multiple sclerosis. Many other cytokines are being studied.

Anakinra, used to treat RA, is a recombinant, slightly modified form of the naturally occurring IL-1R antagonist; this drug attaches to the IL-1 receptor and thus prevents binding of IL-1, but unlike IL-1, it does not activate the receptor.

Cells expressing cytokine receptors can be targeted by modified versions of the relevant cytokine (eg, denileukin diftitox, which is a fusion protein containing sequences from IL-2 and from diphtheria toxin). Denileukin is used in cutaneous T-cell lymphoma to target the toxin to cells expressing the CD25 component of the IL-2 receptor.

Small-molecule mimetics

Small linear peptides, cyclicized peptides, and small organic molecules are being developed as agonists or antagonists for various applications. Screening libraries of peptides and organic compounds can identify potential mimetics (eg, agonists for receptors for erythropoietin, thrombopoietin, and G-CSF).

Cellular therapies

Immune system cells are harvested (eg, by leukaphoresis) and activated in vitro before they are returned to the patient. The aim is to amplify the normally inadequate natural immune response to prostate cancer. Methods of activating immune cells include using cytokines to stimulate and increase numbers of antitumor cytotoxic T cells and using pulsed exposure to antigen-presenting cells such as dendritic cells with tumor antigens.

Last full review/revision November 2012 by Peter J. Delves, PhD